CN112237573A - Tablet containing finerenone and preparation method thereof - Google Patents
Tablet containing finerenone and preparation method thereof Download PDFInfo
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- CN112237573A CN112237573A CN202011182013.7A CN202011182013A CN112237573A CN 112237573 A CN112237573 A CN 112237573A CN 202011182013 A CN202011182013 A CN 202011182013A CN 112237573 A CN112237573 A CN 112237573A
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- finerenone
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- BTBHLEZXCOBLCY-QGZVFWFLSA-N (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide Chemical compound C1([C@@H]2C(=C(C)NC=3C(C)=CN=C(C2=3)OCC)C(N)=O)=CC=C(C#N)C=C1OC BTBHLEZXCOBLCY-QGZVFWFLSA-N 0.000 title claims abstract description 48
- 229950004408 finerenone Drugs 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000011248 coating agent Substances 0.000 claims abstract description 32
- 238000000576 coating method Methods 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 14
- 239000011247 coating layer Substances 0.000 claims abstract description 11
- 239000000945 filler Substances 0.000 claims abstract description 9
- 239000000314 lubricant Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000000853 adhesive Substances 0.000 claims abstract description 5
- 230000001070 adhesive effect Effects 0.000 claims abstract description 5
- 239000002245 particle Substances 0.000 claims description 32
- 238000002156 mixing Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 13
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 12
- 229920000881 Modified starch Polymers 0.000 claims description 10
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 10
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229960000913 crospovidone Drugs 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000007873 sieving Methods 0.000 claims description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920002261 Corn starch Polymers 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000008120 corn starch Substances 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 238000005550 wet granulation Methods 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 14
- 229920003081 Povidone K 30 Polymers 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 229960001208 eplerenone Drugs 0.000 description 5
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 5
- 229960002256 spironolactone Drugs 0.000 description 5
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 5
- 238000009507 drug disintegration testing Methods 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 2
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 2
- 229940083712 aldosterone antagonist Drugs 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical group OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a tablet containing finenone and a preparation method thereof. The tablet containing the finerenone comprises a medicine tablet core and a coating layer, wherein the medicine tablet core is composed of the following raw materials in parts by weight: 5-30 parts of Finorenone, 85-135 parts of filler, 5-7 parts of disintegrating agent, 5-7 parts of adhesive, 0.3-1 part of solubilizer and 0.6-1.2 parts of lubricant; the coating layer is a water-soluble coating material. The tablet containing the finerenone has good dissolution performance and high stability, and can realize good dissolution effect under various media.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a tablet containing finenone and a preparation method thereof.
Background
Aldosterone receptor antagonists currently in use are spironolactone (generation 1), eplerenone (generation 2), and the like. Large-scale clinical tests show that spironolactone and eplerenone can obviously improve the prognosis of patients with heart failure and improve the survival rate, but the spironolactone and eplerenone have low selectivity and possibly cause adverse reactions such as the rise of the blood potassium level of the patients and the like, and people do not use the spironolactone and eplerenone as first-line medicaments. Finorenone is a third generation aldosterone receptor antagonist and has the structural formula:
finerenone binds in the ligand binding domain of MR in a different way than steroid mineralocorticoid receptor antagonists and exhibits a high binding rate, the concentration of antagonist required to inhibit 50% of receptor activation being only 17.8nm, while spironolactone and eplerenone are 24nm and 990nm, respectively; furthermore, equivalent distribution of finerenone in heart and kidney is achieved, while steroidal mineralocorticoid antagonists are more abundant in kidney, and thus finerenone represents a more potent mineralocorticoid receptor antagonist. At present, no patent or literature discloses a prescription and a process related to the finenone tablet in China.
Disclosure of Invention
The invention aims to provide a tablet containing finerenone and a preparation method which can produce a tablet with good dissolution performance and high stability and can realize good dissolution under various media.
The tablet containing finenone comprises a medicine tablet core and a coating layer, wherein the medicine tablet core is composed of the following raw materials in parts by weight:
the coating layer is a water-soluble coating material.
The granularity of the Finorenone is D50-82 μm, and D90-35 μm.
The filler is one or more of microcrystalline cellulose, lactose, corn starch and pregelatinized starch; a mixture of microcrystalline cellulose and pregelatinized starch is preferred.
The disintegrant is one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and corn starch; crospovidone is preferred.
The adhesive is one or more of polyvidone K30, hydroxypropyl cellulose, and sodium carboxymethylcellulose; povidone K30 is preferred.
The solubilizer is one or more of sodium dodecyl sulfate, tween 20 and poloxamer; sodium lauryl sulfate is preferred.
The lubricant is one or more of magnesium stearate, talcum powder and superfine silica gel powder; talc powder is preferred.
The mass of the coating layer is 1-4% of the mass of the drug tablet core.
Preferably, the pharmaceutical core of said finerenone-containing tablets is formulated as follows:
the preparation method of the tablet containing the finerenone adopts a wet granulation process and comprises the following steps:
(1) micronizing the finenone to obtain a particle size D50 of 35 μm or less and a particle size D90 of 82 μm or less;
(2) adding the micronized finerenone, the adhesive and the solubilizer into purified water to prepare a particle solution;
(3) putting the filler and the disintegrant into a wet granulating machine, mixing uniformly, and adding the granular solution for granulating;
(4) sieving the prepared granules with a 60-mesh sieve, grading and drying;
(5) putting the lubricant and the dried particles into a three-dimensional mixer, and uniformly mixing;
(6) and (5) tabletting the material obtained in the step (5), and coating with a coating solution to obtain the tablets containing the finenone.
In the step (2), the mass ratio of the purified water to the finenone is 15:1-20: 1.
In the step (6), the coating solution is prepared from the following raw materials in parts by weight:
5-7 parts of water-soluble coating material
30-60 parts of a coating solvent;
the water-soluble coating material is Opadry;
the coating solvent is water, ethanol or a mixture of water and ethanol, preferably a mixture of water and ethanol, and the mixing volume ratio of the water to the ethanol is 6:1-1: 1.
Preferably, the preparation method of the tablet containing the finerenone comprises the following steps:
(1) micronizing the finenone to obtain a particle size D50 of 35 μm or less and a particle size D90 of 82 μm or less;
(2) adding the micronized finenone, the adhesive and the solubilizer into purified water to prepare a particle solution;
(3) putting filler and disintegrant into wet granulating machine, stirring at low cut and low temperature for 10-30min, mixing, adding granule solution, stirring at low cut and high temperature for 5-15min, and granulating;
(4) sieving the prepared granules with a 60-mesh sieve, grading and drying;
(5) putting the lubricant and the dried particles into a three-dimensional mixer, mixing for 10-30min at the rotating speed of 10-30rpm, and uniformly mixing;
(6) and (3) adding the material obtained in the step (5) into a tablet machine for tabletting, controlling the tabletting hardness to be 2-10kg, and coating with a coating solution in coating equipment to obtain the tablets containing the finenone.
In the step (3), the low-speed stirring of low-cutting and low-stirring is 150r/min, and the low-speed shearing is 1500 r/min; the stirring speed of low-shear high-stirring is 300r/min, and the shearing speed is 1500 r/min.
In the preparation process, the finerenone needs to be micronized to reach a certain granularity, the content of the main drugs is more uniform after mixing, and the prepared tablet is more fine and uniform; wherein the dissolution rate of the finerenone is greatly accelerated, and the smaller the granularity is, the larger the surface area is, and the faster the dissolution is, for the same weight of the medicine. The sodium dodecyl sulfate, the micronized finerenone and the povidone K30 are added into purified water to prepare a granular solution, and if the finerenone is not distributed sufficiently, the content uniformity of the tablet is unqualified.
Compared with the prior art, the invention has the following beneficial effects:
(1) the tablet containing the finenone prepared by the invention has stable quality, the curative effect and performance index of the medicine are similar to those of the original preparation, but the price is much lower than that of the original preparation, and the economic pressure of a patient is greatly reduced;
(2) the tablet containing the finenone prepared by the invention has good process tolerance and high stability;
(3) the tablet containing the finerenone prepared by the invention has better uniformity in dissolution batches and high bioavailability.
Detailed Description
The present invention will be further described with reference to the following examples.
Examples 1 to 4
In the tablet core formulas of examples 1-4, the sizes of the finenone micropowder particles are different, and the influence of the sizes of the finenone micropowder particles on the dissolution rate of the drug is examined. The tablet core formulations of examples 1-4 are shown in table 1.
TABLE 1 pharmaceutical tablet core formulations of examples 1-4
Tablets containing finenone were prepared according to the above formula as follows:
(1) micronizing the finenone to the corresponding particle size of each example;
(2) adding the micronized finenone, povidone K30 and sodium dodecyl sulfate into 150mg of purified water to prepare a particle solution;
(3) putting microcrystalline cellulose, pregelatinized starch and crospovidone into a wet granulating machine, stirring at low shear and low speed (150 r/min at low speed and 1500r/min) for 20min, mixing, adding the granule solution, stirring at low shear and high speed (300 r/min at high speed and 1500r/min) for 10min, and granulating;
(4) sieving the prepared granules with a 60-mesh sieve, grading and drying;
(5) putting the talcum powder and the dried particles into a three-dimensional mixer, and mixing at the rotating speed of 20rpm for 20min to be uniform;
(6) and (3) adding the material obtained in the step (5) into a tablet press for tabletting, controlling the tabletting hardness to be 6kg, coating the tablets with a coating solution (mixing Opadry, water and ethanol according to the mass ratio of 1:5: 2) in a coating device, and controlling the mass of a coating layer to be 2% of the mass of the drug tablet core to obtain the tablets containing the finerenone.
The tablets containing finerenone obtained in examples 1 to 4 were subjected to dissolution tests in the following manner:
according to the second method of 0931 of the general rules of the four parts of the pharmacopoeia 2015 edition, 900mL of water is taken as a dissolution medium, the rotating speed is 75r/min, 10mL of the solution is taken at 5, 10, 15, 30, 45 and 60min, the dissolution medium with the same volume and the same temperature is supplemented at the same time, and the solution is filtered by a microporous membrane, and the subsequent filtrate is taken as a sample solution. The dissolution of each batch is shown in table 2.
TABLE 2 dissolution test results for tablets containing finerenone prepared in examples 1-4
And (4) conclusion: according to the dissolution result, the raw material medicine finerenone is micronized to the particle size D50 which is less than or equal to 35 mu m, D90 which is less than or equal to 82 mu m, and the 15-minute accumulated dissolution rate is more than 85 percent when the particle size is finer, so that the dissolution requirement can be met when the particle size of the finerenone is D50 which is less than or equal to 35 mu m and D90 which is less than or equal to 82 mu m.
Examples 5 to 8
The pharmaceutical tablet formulations of examples 5-8 were varied in the type and amount of filler and disintegrant to examine the effect of filler and disintegrant on the disintegration time of the drug, and the pharmaceutical tablet formulations and disintegration times of the drugs of examples 5-8 are shown in Table 3.
The preparation method of the tablets containing finerenone comprises the following steps:
(1) micronizing the finenone to obtain a particle size D50 of 35 μm or less and a particle size D90 of 82 μm or less;
(2) adding the micronized finenone, povidone K30 and sodium dodecyl sulfate into 200mg of purified water to prepare a particle solution;
(3) putting microcrystalline cellulose, pregelatinized starch and disintegrant (crospovidone or croscarmellose sodium) into wet granulating machine, stirring at low speed (150 r/min and 1500r/min) for 20min, mixing, adding granule solution, stirring at low speed (300 r/min and 1500r/min) for 10min, and granulating;
(4) sieving the prepared granules with a 60-mesh sieve, grading and drying;
(5) putting the talcum powder and the dried particles into a three-dimensional mixer, and mixing at the rotating speed of 20rpm for 20min to be uniform;
(6) and (3) adding the material obtained in the step (5) into a tablet press for tabletting, controlling the tabletting hardness to be 6kg, coating by using a coating solution (mixing Opadry, water and ethanol according to the mass ratio of 1:3.5: 3.5) in a coating device, and controlling the mass of a coating layer to be 3% of the mass of the drug tablet core to obtain the tablet containing the finerenone.
Table 3 pharmaceutical tablet core formulations and drug disintegration times for examples 5-8
| Item | Example 5 | Example 6 | Example 7 | Example 8 |
| Finerenone(mg) | 10 | 10 | 10 | 10 |
| Microcrystalline cellulose (mg) | 78 | 78 | 76 | 83.5 |
| Pregelatinized starch (mg) | 29.5 | 29.5 | 29.5 | 37 |
| Polyvinylpolypyrrolidone (mg) | 5 | / | 7 | 7 |
| Croscarmellose sodium (mg) | / | 5 | / | / |
| Povidone K30(mg) | 6 | 6 | 6 | 6 |
| Sodium dodecyl sulfate (mg) | 0.65 | 0.65 | 0.65 | 0.65 |
| Talcum powder (mg) | 0.85 | 0.85 | 0.85 | 0.85 |
| Disintegration time(s) | 111 | 120 | 103 | 129 |
And (4) conclusion: through the investigation of the types and the dosage of the filling agent and the disintegrating agent, the disintegrating agent is preferably crospovidone, and the disintegration speed is obviously reduced when the dosage of the pregelatinized starch is too much.
Examples 9 to 12
The drug core formulations of examples 9 to 12 were different in the kind, amount and mode of addition of the solubilizing agent for examining the effect of the solubilizing agent on the drug disintegration time, and the drug core formulations, the mode of addition of the solubilizing agent and the drug disintegration time of examples 9 to 12 are shown in Table 4.
The preparation method of the tablets containing finerenone comprises the following steps:
(1) micronizing the finenone to obtain a particle size D50 of 35 μm or less and a particle size D90 of 82 μm or less;
(2) adding the micronized finerenone, povidone K30 and solubilizer (sodium dodecyl sulfate or poloxamer) into 170mg of purified water to prepare a particle solution;
(3) putting microcrystalline cellulose, pregelatinized starch, crospovidone and solubilizer (sodium dodecyl sulfate) into a wet granulator, stirring at low speed of 150r/min for 20min, mixing, adding the granule solution, stirring at high speed of 300r/min for 10min, and granulating;
(4) sieving the prepared granules with a 60-mesh sieve, grading and drying;
(5) putting the talcum powder and the dried particles into a three-dimensional mixer, mixing for 10min at the rotating speed of 30rpm, and uniformly mixing;
(6) and (3) adding the material obtained in the step (5) into a tablet press for tabletting, controlling the tabletting hardness to be 6kg, coating the tablets with a coating solution (mixing Opadry, water and ethanol according to the mass ratio of 1:4: 3) in a coating device, and controlling the mass of a coating layer to be 4% of the mass of the drug tablet core to obtain the tablets containing the finerenone.
TABLE 4 pharmaceutical tablet core formulations, solubilizer addition and drug disintegration times of examples 9-12
And (4) conclusion: through the investigation on the type, the amount and the adding mode of the solubilizer, the solubilizer is preferably lauryl sodium sulfate, and the solubilizer and the finerenone and the povidone K30 which are subjected to micro-powder are added into purified water together to prepare a granular solution, so that the disintegration speed is obviously improved.
Examples 13 to 14
The tablet core formulations of examples 13-14 are shown in Table 5.
TABLE 5 pharmaceutical core formulations of examples 13-14
| Prescription | Example 13 | Example 14 |
| Finerenone(mg) | 10 | 20 |
| Microcrystalline cellulose (mg) | 72.2 | 73.2 |
| Pregelatinized starch (mg) | 35 | 22 |
| Polyvinylpolypyrrolidone (mg) | 6.5 | 7 |
| Povidone K30(mg) | 5 | 6 |
| Sodium dodecyl sulfate (mg) | 0.4 | 0.6 |
| Talcum powder (mg) | 0.9 | 1.2 |
The preparation method of the tablets containing finerenone comprises the following steps:
(1) micronizing the finenone to obtain a particle size D50 of 35 μm or less and a particle size D90 of 82 μm or less;
(2) adding the micronized finerenone, povidone K30 and solubilizer (sodium dodecyl sulfate or poloxamer) into 160mg of purified water to prepare a particle solution;
(3) putting microcrystalline cellulose, pregelatinized starch, crospovidone and solubilizer (sodium dodecyl sulfate) into a wet granulator, stirring at low speed of 150r/min for 20min, mixing, adding the granule solution, stirring at high speed of 300r/min for 10min, and granulating;
(4) sieving the prepared granules with a 60-mesh sieve, grading and drying;
(5) putting talcum powder and the dried particles into a three-dimensional mixer, mixing at the rotating speed of 10rpm for 20min, and uniformly mixing;
(6) and (3) adding the material obtained in the step (5) into a tablet press for tabletting, controlling the tabletting hardness to be 8kg, coating the tablets with a coating solution (mixing Opadry, water and ethanol according to the mass ratio of 1:6: 1) in a coating device, and controlling the mass of a coating layer to be 1% of the mass of the drug tablet core to obtain the tablets containing the finerenone.
Example 15
The tablets containing finerenone prepared in example 13 were subjected to a stability test as follows:
(1) the samples prepared in example 13 were respectively placed at a high temperature of 60 deg.C, 25 deg.C/RH 92.5% and illuminated (total illumination was not less than 1.2X 10)6Lux hr) were sampled at 5d and 10d, and the results of the test were shown in table 6, comparing with 0 d.
Table 6 stability test results for the tablets containing finerenone prepared in example 13
(2) The samples prepared in example 13 were sampled at 1M, 2M, 3M and 6M at 40 ℃. + -. 2 ℃/RH 75%. + -. 5% and compared with the 0M results, and the results are shown in Table 7.
Table 7 stability test results for the tablets containing finerenone prepared in example 13
And (4) conclusion: the related substances and content results of the pharmaceutical composition provided by the invention in the processes of influencing factors and accelerated stability tests are not obviously changed compared with 0d, so that the finerenone tablet and the product prepared by the preparation method provided by the invention have better stability.
Claims (10)
1. A tablet comprising finerenone characterized by: the drug core is composed of the following raw materials in parts by weight:
the coating layer is a water-soluble coating material.
2. The finerenone-containing tablet according to claim 1, characterized in that: the granularity of the Finorenone is D50-82 μm, and D90-35 μm.
3. The finerenone-containing tablet according to claim 1, characterized in that: the filler is one or more of microcrystalline cellulose, lactose, corn starch, and pregelatinized starch.
4. The finerenone-containing tablet according to claim 1, characterized in that: the disintegrant is one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and corn starch.
5. The finerenone-containing tablet according to claim 1, characterized in that: the binder is one or more of polyvidone K30, hydroxypropyl cellulose, and sodium carboxymethylcellulose.
6. The finerenone-containing tablet according to claim 1, characterized in that: the solubilizer is one or more of sodium dodecyl sulfate, Tween 20 and poloxamer.
7. The finerenone-containing tablet according to claim 1, characterized in that: the lubricant is one or more of magnesium stearate, pulvis Talci, and silica gel.
8. The finerenone-containing tablet according to claim 1, characterized in that: the mass of the coating layer is 1-4% of the mass of the drug tablet core.
9. A process for the preparation of a finerenone-containing tablet according to any one of claims 1 to 8, characterized in that: adopts a wet granulation process, and comprises the following steps:
(1) micronizing the finenone to obtain a particle size D50 of 35 μm or less and a particle size D90 of 82 μm or less;
(2) adding the micronized finerenone, the adhesive and the solubilizer into purified water to prepare a particle solution;
(3) putting the filler and the disintegrant into a wet granulating machine, mixing uniformly, and adding the granular solution for granulating;
(4) sieving the prepared granules with a 60-mesh sieve, grading and drying;
(5) putting the lubricant and the dried particles into a three-dimensional mixer, and uniformly mixing;
(6) and (5) tabletting the material obtained in the step (5), and coating with a coating solution to obtain the tablets containing the finenone.
10. The process for the preparation of a finerenone-containing tablet according to claim 9, characterized in that: in the step (6), the coating solution is prepared from the following raw materials in parts by weight:
5-7 parts of water-soluble coating material
30-60 parts of a coating solvent;
the water-soluble coating material is Opadry;
the coating solvent is water, ethanol or mixture of water and ethanol.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106795155A (en) * | 2014-08-01 | 2017-05-31 | 拜耳医药股份有限公司 | Prepare the method for the formamide of 2,81,6 naphthyridines of dimethyl Isosorbide-5-Nitrae dihydro of (4S) 4 (methoxyphenyl of 4 cyano group 2) 5 ethyoxyl 3 and its purify for use as active medicine active component |
| US20190262340A1 (en) * | 2016-10-11 | 2019-08-29 | Bayer Pharama Aktiengesellschaft | Combination containing sgc stimulators and mineralocorticoid receptor antagonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106795155A (en) * | 2014-08-01 | 2017-05-31 | 拜耳医药股份有限公司 | Prepare the method for the formamide of 2,81,6 naphthyridines of dimethyl Isosorbide-5-Nitrae dihydro of (4S) 4 (methoxyphenyl of 4 cyano group 2) 5 ethyoxyl 3 and its purify for use as active medicine active component |
| US20190262340A1 (en) * | 2016-10-11 | 2019-08-29 | Bayer Pharama Aktiengesellschaft | Combination containing sgc stimulators and mineralocorticoid receptor antagonists |
Non-Patent Citations (1)
| Title |
|---|
| SILVIA LENTINI ETAL.: "Pharmacokinetics, safety and tolerabilityof the novel, selective mineralocorticoidreceptor antagonist finerenone–resultsfrom first-in-man and relativebioavailability studies", 《FUNDAMENTAL & CLINICAL PHARMACOLOGY》, vol. 30, pages 172 * |
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